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<h1>Osteoporosis, harmful calcification, and nerve/muscle malfunctions</h1>
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<div style="text-align: center;">
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<a href="/"><img class="epic" src="/icons/chads/chad.png"></a>
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<hr>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
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<p>From the <a href="https://raypeat.com/articles/articles/osteoporosis.shtml" target="_blank">original article</a> in 2006. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
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<p>During
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pregnancy, a woman's ability to retain dietary calcium and iron increases,
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and the baby seems to be susceptible to overloading. A normal baby doesn't
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need dietary iron for several months, as it uses the iron stored in
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its tissue, and recently it has been reported that normal fetuses and
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babies may have calcified pituitary glands. Pituitary cell death is
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sometimes seen with the concretions. (Groisman, et al.) Presumably,
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the calcification is resorbed as the baby grows. This is reminiscent
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of the "age pigment" that can be found in newborns, representing
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fetal stress from hypoxia, since that too disappears shortly after birth.
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Iron overload, age pigment, and calcification of soft tissues are so
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commonly associated with old age, that it is important to recognize
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that the same cluster occurs at the other extreme of (young) age, and
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that respiratory limitations characterize both of these periods of life.
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</p>
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<p>Calcium
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is probably the most popular element in physiological research, since
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it functions as a regulatory trigger in many cell processes, including
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cell stimulation and cell death. Its tendency to be deposited with iron
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in damaged tissue has often been mentioned. In hot weather, chickens
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pant to cool themselves, and this can lead to the production of thin
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egg shells. Carbonated water provides enough carbon dioxide to replace
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that lost in panting, and allows normal calcification of the shells.
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[Science 82, May, 1982] The deposition of calcium is the last phase
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of the "tertiary coat" of the egg, to which the oviduct glands
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successively add albumin, "egg membrane," and the shell, containing
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matrix proteins (including some albumin; Hincke, 1995) and calcium crystals.
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Albumin is the best understood of these layers, but it is still complex
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and mysterious; its unusual affinity for metal ions has invited comparisons
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with proteins of the immune system. It is known to be able to bind iron
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strongly, and this is considered to have an "immunological"
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function, preventing the invasion of organisms that depend on iron.
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Maria de Sousa ("Iron and the lymphomyeloid system: A growing knowledge,"
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Iron in Immunity, Cancer and Inflammation, ed. by M. de Sousa and J.
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H. Brock, Wiley & Sons, 1989) has argued that the oxygen delivery
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system and the immune system evolved together, recycling iron in a tightly
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controlled system. </p>
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<p>The
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role of macrophages in the massive turnover of hemoglobin, and as osteoclasts,
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gives us a perspective in which iron and calcium are handled in analogous
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ways. Mechnikov's view of the immune system, growing from his observations
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of the "phagocytes," similarly gave it a central role in the
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organism as a form-giving/ nutrition-related process. In a family with
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"marble-bone disease," or osteopetrosis, it was found that
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their red blood cells lacked one form of the carbonic anhydrase enzyme,
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and that as a result, their body fluids retained abnormally high concentrations
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of carbon dioxide. Until these people were studied, it had been assumed
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that an excess of carbon dioxide would have the opposite effect, dissolving
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bones and causing osteoporosis or osteopenia, instead of osteopetrosis.
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The thyroid hormone is responsible for the carbon dioxide produced in
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respiration. Chronic hypothyroidism causes osteopenia, and in this connection,
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it is significant that women (as a result of estrogen's effects on the
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thyroid) are much more likely than men to be hypothyroid, and that,
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relative to men, women in general are "osteopenic," that is,
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they have more delicate skeletons than men do. </p>
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<p>In
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an experiment, rats were given a standard diet, to which had been added
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1% Armour thyroid, that is, they were made extremely hyperthyroid. Since
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their diet was inadequate (later experiments showed that this amount
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of thyroid didn't cause growth retardation when liver was added to the
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diet) for their high metabolic rate, they died prematurely, in an apparently
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undernourished state, weighing much less than normal rats. Their bones,
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however, were larger and heavier than the bones of normal rats. A few
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incompetent medical "studies" have made people fear that "taking
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thyroid can cause osteoporosis." Recognizing that hypothyroid women
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are likely to have small bones and excessive cortisol production, the
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inadequate treatment of hypothyroidism with thyroxin (the thyroid-suppressive
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precursor material), is likely to be associated with relative osteoporosis,
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simply because it doesn't correct hypothyroidism. Similar misinterpretations
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have led people to see an association between "thyroid use"
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(generally thyroxin) and breast cancer--hypothyroid women are likely
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to have cancer, osteoporosis, obesity, etc., and are also likely to
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have been inadequately treated for hypothyroidism. T3, the active form
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of thyroid hormone, does contribute to bone formation. (For example,
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M. Alini, et al.) </p>
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<p>Around
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the same time (early 1940s) that the effects of thyroid on bone development
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were being demonstrated, progesterone was found to prevent age-related
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changes in bones, and "excessive" seeming doses of thyroid
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were found to prevent age-related joint diseases in rats.
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</p>
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<p>A
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logical course of events, building on these and subsequent discoveries,
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would have been to observe that the glucocorticoids cause a negative
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calcium balance, leading to osteoporosis, and that thyroid and progesterone
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oppose those hormones, protecting against osteoporosis. But the drug
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industry had discovered the profits in estrogen ("the female hormone")
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and the cortisone-class of drugs. Estrogen was promoted to prevent miscarriages,
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to stop girls (and boys) from growing too tall, to cure prostate and
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breast cancer, to remedy baldness, and 200 other absurdities. As all
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of those frauds gradually became untenable, even in the commercial medical
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culture, the estrogen industry began to concentrate on osteoporosis
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and femininity. Heart disease and Alzheimer's disease back those up.</p>
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<p>"If estrogen causes arthritis,
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prescribe prednisone for the inflammation. If prednisone causes osteoporosis,
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increase the dose of estrogen to retard the bone-loss. People are tough,
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and physiological therapies aren't very profitable."
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</p>
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<p>Fifteen
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years ago I noted in a newsletter that hip fractures most often occur
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in frail, underweight old women, and that heavier, more robust women
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seem to be able to bear more weight with less risk of fracture. Although
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I hadn't read it at the time, a 1980 article (Weiss, et al.) compared
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patients with a broken hip or arm with a control group made up of hospitalized
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orthopedic patients with problems other than hip or arm fractures. The
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fracture cases' weight averaged 19 pounds lighter than that of the other
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patients. They were more than 3.6 times as likely to be alcoholic or
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epileptic. It would be fair to describe them as a less robust group.
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</p>
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<p>Since
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the use of estrogen has become so common in the U.S., it is reasonable
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to ask whether the incidence of hip fractures in women over 70 has declined
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in recent decades. If estrogen protects against hip fractures, then
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we should see a large decrease in their incidence in the relevant population.
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</p>
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<p>Hip
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fractures, like cancer, strokes, and heart disease, are strongly associated
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with old age. Because of the baby-boom, 1945 to 1960, our population
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has a bulge, a disproportion in people between the ages of 35 and 50,
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and those older. Increasingly, we will be exposed to publicity about
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the declining incidence of disease, fraudulently derived from the actually
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declining proportion of old people. For example, analyzing claims based
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on the pretense that the population bulge doesn't exist, I have seen
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great publicity given to studies that would imply that our life-expectancy
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is now 100 years, or more. </p>
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<p>Comparing
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the number of hip fractures, per 1000 75 year old women, in 1996, with
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the rate in 1950, we would have a basis for judging whether estrogen
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is having the effect claimed for it. </p>
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<p>The
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x-ray data seem to convince many people estrogen is improving bone health,
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by comparing measurements in the same person before and after treatment.
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Does estrogen cause water retention? Yes. Does tissue water content
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increase measured bone density? Yes. Are patients informed that their
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"bone scans" don't have a scientific basis? No. The calcification
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of soft tissues under the influence of estrogen must also be taken into
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account in interpreting x-ray evidence. (Hoshino, 1996) Granted that
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woman who are overweight have fewer hip fractures (and more cancer and
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diabetes), what factors are involved? Insulin is the main factor promoting
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fat storage, and it is anabolic for bone. (Rude and Singer, "Hormonal
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modifiers of mineral metabolism.") The greatest decrease in bone
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mass resulting from insulin deficiency was seen in white females, and
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after five years of insulin treatment, there was a lower incidence of
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decreased bone mass (Rosenbloom, et al., 1977). McNair, et al. (1978
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and 1979) found that the loss of bone mass coincided with the onset
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of clinical diabetes. Since excess cortisol can cause both high blood
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sugar and bone loss, when diabetes is defined on the basis of high blood
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sugar, it will often involve high blood sugar caused by excess cortisol,
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and there will be calcium loss. Elsewhere, I have pointed out some of
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the similarities between menopause and Cushing's syndrome; a deficiency
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of thyroid and progesterone can account for many of these changes. Nencioni
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and Polvani have observed the onset of progesterone deficiency coinciding
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with bone loss, and have emphasized the importance of progesterone's
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antagonism to cortisol. </p>
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<p>Johnston
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(1979) found that progesterone (but not estrone, estradiol, testosterone,
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or androstenedione) was significantly lower in those losing bone mass
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most rapidly. </p>
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<p>Around
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the age of 50, when bone loss is increasing, progesterone and thyroid
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are likely to be deficient, and cortisol and prolactin are likely to
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be increased. Prolactin contributes directly to bone loss, and is likely
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to be one of the factors that contributes to decreased progesterone
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production. </p>
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<p>Estrogen
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tends to cause increased secretion of prolactin and the glucocorticoids,
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which cause bone loss, but it also promotes insulin secretion, which
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tends to prevent bone loss. All of these factors are associated with
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increased cancer risk. </p>
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<p>Thyroid
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and progesterone, unlike estrogen, stimulate bone-building, and are
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associated with a decreased risk of cancer. It seems sensible to use
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thyroid and progesterone for their general anti-degenerative effects,
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protecting the bones, joints, brain, immune system, heart, blood vessels,
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breasts, etc. </p>
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<p>But
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the issue of calcification/decalcification is so general, we mustn't
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lose interest just because the practical problem of osteoporosis is
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approaching solution. </p>
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<p>For
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example, healthy high energy metabolism requires the exclusion of most
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calcium from cells, and when calcium enters the stimulated or deenergized
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cell, it is likely to trigger a series of reactions that lower energy
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production, interfering with oxidative metabolism. During aging, both
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calcium and iron tend to accumulate and they both seem to have an affinity
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for similar locations, and they both tend to displace copper. (Compare
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K. Sato, et al., on the calcification of copper-containing paints.)
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Elastin is a protein, the units of which are probably bound together
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by copper atoms. In old age, elastin is one of the first substances
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to calcify, for example in the elastic layers of arteries, causing them
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to lose elasticity, and to harden into almost bone-like tubes. In the
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heart and kidneys, the mitochondria (rich in copper-enzymes) are often
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the location showing the earliest calcification, for example when magnesium
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is deficient. </p>
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<p>Obviously,
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certain proteins have higher than average affinity for copper, iron,
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and calcium. For example, egg-white's unusual behavior with copper can
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be seen if you make a meringue in a copper pan--the froth is unusually
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firm. My guess is that copper atoms bind the protein molecules into
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relatively elastic systems. In many systems, calcium forms the link
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between adhesive proteins. </p>
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<p>In
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brain degeneration, the regions that sometimes accumulate aluminum,
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will accumulate other metals instead, if they predominate in the environment;
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calcium is found in this part of the brain in some of the Pacific regions
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studied by Gajdusek. Certain cells in the brain used to be called "metalophils,"
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because they could be stained intensely with silver and other metals;
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I suppose these are part of the immune system, handling iron as described
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by Maria de Sousa. Macrophages have been proposed as an important factor
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in producing atherosclerotic plaques (Carpenter, et al.). There is evidence
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that they (and not smooth muscle cells) are the characteristic foam
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cells, and their conversion of polyunsaturated oils into age pigment
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accounts for the depletion of those fats in the plaques. The same evidence
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could be interpreted as a defensive reaction, binding iron and destroying
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unsaturated fatty acids, and by this detoxifying action, possibly protecting
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against calcification and destruction of elastin. (This isn't the first
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suggestion that atherosclerosis might represent a protective process;
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see S. M. Plotnikov, et al., 1994.) </p>
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<p>Since
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carbon dioxide and bicarbonate are formed in the mitochondria, it is
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reasonable to suppose that the steady outward flow of the bicarbonate
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anion would facilitate the elimination of calcium from the mitochondria.
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Since damaged mitochondria are known to start the process of pathological
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calcification in the heart and kidneys, it probably occurs in other
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tissues that are respiratorily stressed. And if healthy respiration,
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producing carbon dioxide, is needed to keep calcium outside the cell,
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an efficient defense system could also facilitate the deposition of
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calcium in suitable places--depending on specific protein binding. The
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over-grown bones in the hyperthyroid rats and the women with osteopetrosis
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suggest that an abundance of carbon dioxide facilitates bone formation.
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Since no ordinary inorganic process of precipitation/crystallization
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has been identified that could account for this, we should consider
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the possibility that the protein matrix is regulated in a way that promotes
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(or resists) calcification. The affinity of carbon dioxide for the amine
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groups on proteins (as in the formation of carbamino hemoglobin, which
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changes the shape of the protein) could change the affinity of collagen
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or other proteins for calcium. Normally, ATP is considered to be the
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most important substance governing such changes of protein conformation
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or binding properties, but ordinarily, ATP and CO2 are closely associated,
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because both are produced in respiration. Gilbert Ling has suggested
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that hormones such as progesterone also act as cardinal adsorbants,
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regulating the affinity of proteins for salts and other molecules.
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</p>
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<p>Cells
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have many proteins with variable affinity for calcium; for example in
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muscle, a system called the endoplasmic reticulum, releases and then
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sequesters calcium to control contraction and relaxation. (This calcium-binding
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system is backed up by--and is spatially in close association with--that
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of the mitochondrion.) Ion-exchange resins can be chemically modified
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to change their affinity for specific ions, and molecules capable of
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reacting strongly with proteins can change the affinities of the proteins
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for minerals. What evidence is there that carbon dioxide could influence
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calcium binding? The earliest deposition of crystals on implanted material
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is calcium carbonate. (J. Vuola, et al, 1996.) In newly formed bone,
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the phosphate content is low, and increases with maturity. While mature
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bone has an apatite-like ratio of calcium and phosphate, newly calcified
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bone is very deficient in phosphate (according to Dallemagne, the initial
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calcium to phosphorus ratio is 1.29, and it increases to 2.20.) (G.
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Bourne, 1972; Dallemagne.) </p>
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<p>The
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carbonate content of bone is often ignored, but in newly formed bone,
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it is probably the pioneer. Normally, "nucleation" of crystals
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is thought of as a physical event in a supersaturated solution, but
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the chemical interaction between carbon dioxide and amino groups (amino
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acids, protein, or ammonia, for example) removes the carbon dioxide
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from solution, and the carbamino acid formed becomes a bound anion with
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which calcium can form a salt. With normal physiological buffering,
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the divalent calcium (Ca2+) should form a link between the monovalent
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carbamino acid and another anion. Linking with carbonate (CO32-), one
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valence would be free to continue the salt-chain. This sort of chemistry
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is compatible with the known conditions of bone formation.
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</p>
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<p>Klein,
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et al. (1996), think of uncoupled oxidative phosphorylation in terms
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of "subtle thermogenesis," which isn't demonstrated in their
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experiment, but their experiment actually suggests that stimulated production
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of carbon dioxide is the factor that stimulates calcification. Their
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experiment seems to be the in vitro equivalent of the various observations
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mentioned above. DHEA, which powerfully stimulates bone formation, is
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(like thyroid and progesterone) thermogenic, but in these cases, the
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relevant event is probably the stimulation of respiration, not the heat
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production. In pigs (Landrace strain) susceptible to malignant hyperthermia,
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there is slow removal of calcium from the contractile apparatus of their
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muscles. Recent evidence shows that an extramitochondrial NADH-oxidase
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is functioning. This indicates that carbon dioxide production is limited.
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I think this is responsible for the cells' sluggishness in expelling
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calcium. </p>
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<p>Stress-susceptible pigs show abnormalities
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of muscle metabolism (e.g., high lactate formation) that are consistent
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with hypothyroidism. (T. E. Nelson, et al., "Porcine malignant
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hyperthermia: Observations on the occurrence of pale, soft, exudative
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musculature among susceptible pigs," Am. J. Vet. Res. 35, 347-350,
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1974; M. D. Judge, et al., "Adrenal and thyroid function in stress-susceptible
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pigs (Sus domesticus)," Am. J. Physiol. 214(1), 146-151, 1968.)
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</p>
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<p>Malignant
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hyperthermia during surgery is usually blamed on genetic susceptibility
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and sensitivity to anesthetics. (R. D. Wilson, et al., "Malignant
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hyperpyrexia with anesthesia," JAMA 202, 183-186, 1967; B.A Britt
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and W. Kalow, "Malignant hyperthermia: aetiology unknown,"
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Canad. Anaesth. Soc. J. 17, 316-330, 1970.) Hypertonicity of muscles,
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various degrees of myopathy and rigidity, and uncoupling of oxidative
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phosphorylation occur in these people, as in pigs. Lactic acidosis suggests
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that mitochondrial respiration is defective in the people, as in the
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pigs. Besides the sensitivity to anesthetics, the muscles of these people
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are abnormally sensitive to caffeine and elevated extracellular potassium.
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During surgery, artificial ventilation, combined with stress, toxic
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anesthetics, and any extramitochondrial oxidation that might be occurring
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(such as NADH-oxidase, which produces no CO2), make relative hyperventilation
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a plausible explanation for the development of hyperthermia. Hyperventilation
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can cause muscle contraction. Panting causes a tendency for fingers
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and toes to cramp. Free intracellular calcium is the trigger for muscle
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contraction (and magnesium is an important factor in relaxation.) Capillary
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tone, similarly, is increased by hyperventilation, and relaxed by carbon
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dioxide. The muscle-relaxing effect of carbon dioxide shows that the
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binding of intracellular calcium is promoted by carbon dioxide, as well
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as by ATP. The binding of calcium in a way that makes it unable to interfere
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with cellular metabolism is, in a sense, a variant of simple extrusion
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of calcium, and the binding of calcium to extracellular materials. A
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relaxed muscle and a strong bone are characterized by bound calcium.
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</p>
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<p>Activation
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of the sympathetic nervous system promotes hyperventilation. This means
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that hypothyroidism, with high adrenalin (resulting from a tendency
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toward hypoglycemia because of inefficient use of glucose and oxygen),
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predisposes to hyperventilation. </p>
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<p>Muscle
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stiffness, muscle soreness and weakness, and osteoporosis all seem to
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be consequences of inadequate respiration, allowing lactic acid to be
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produced instead of carbon dioxide. Insomnia, hyperactivity, anxiety,
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and many chronic brain conditions also show evidence of defective respiration,
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for example, either slow consumption of glucose or the formation of
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lactic acid, both of which are common consequences of low thyroid function.
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Several studies (e.g., Jacono and Robertson, 1987) suggest that abnormal
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calcium regulation is involved in epilepsy. The combination of supplements
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of thyroid (emphasizing T3), magnesium, progesterone and pregnenolone
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can usually restore normal respiration, and it seems clear that this
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should normalize calcium metabolism, decreasing the calcification of
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soft tissues, increasing the calcification of bones, and improving the
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efficiency of muscles and nerves. (Magnesium, like carbonate, is a component
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of newly formed bone.) The avoidance of polyunsaturated vegetable oils
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is important for protecting respiration; some of the prostaglandins
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they produce have been implicated in osteoporosis, but more generally,
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they antagonize thyroid function and they can interfere with calcium
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control. The presence of the "Mead acid" (the omega-9 unsaturated
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fat our enzymes synthesize) in cartilage suggests a new line of investigation
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regarding the bone-toxicity of the polyunsaturated dietary oils.
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</p>
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<h2>References</h2>
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<small>
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of mitochondrial membrane potential and energy metabolism could be linked
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This uncoupling should be associated with thermogenesis in cells that
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three . . . prehypertrophic chondrocyte subpopulations." "...T3
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pronounced with the most immature cells." "...matrix calcification,
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measured by the incorporation of Ca45(2+) into the cell layer, always
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occurred earlier in cells cultured with T3 compared with T4."</p>
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<p>Y. Seyama, et al., "Effect
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<p>R. Eastell, "Management of
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<p>J. P. Bonjour and R. Rizzoli,
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<p>F. C. Driessens, "Probable
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<p>W. G. Bottje and P. C. Harrison,
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"Effect of carbonated water on growth performance of cockerels
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M. F. Gulyi, "Role of carbonic acid and ammonium nitrogen in regulation
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of metabolism and physiological function in heterotrophic organisms,"
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Ukr. Biokhim. Zh. 52(2), 141-145, 1980.</p>
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<p>K. E. Schaefer, et al., "Effect
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of an increased excretion of titratable acidity, ammonia, and hydrogen
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ion excretion, occurred but was interrupted after the first day....")</p>
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<p>U. F. Rasmussen, et al., "Characterization
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of mitochondria from pig muscle: </p>
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<p>Higher activity of exo-NADH-oxidase
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315(Pt. 2), 659-663, 1996. R. K. Rude and F. R. Singer, "Hormone
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modifiers of mineral metabolism," in Disorders of Mineral Metabolism,
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vol. II: Calcium Physiology, Ed. by F. Bronner and J. W. Coburn, Academic
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|
Press, 1982.</p>
|
|
</small>
|
|
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