Osteoporosis, harmful calcification, and nerve/muscle malfunctions
骨质疏松、有害钙化和神经/肌肉功能障碍
by Raymond Peat
During pregnancy, a woman's ability to retain dietary calcium and iron increases, and the baby seems to be susceptible to overloading. A normal baby doesn't need dietary iron for several months, as it uses the iron stored in its tissue, and recently it has been reported that normal fetuses and babies may have calcified pituitary glands. Pituitary cell death is sometimes seen with the concretions. (Groisman, et al.) Presumably, the calcification is resorbed as the baby grows. This is reminiscent of the “age pigment” that can be found in newborns, representing fetal stress from hypoxia, since that too disappears shortly after birth. Iron overload, age pigment, and calcification of soft tissues are so commonly associated with old age, that it is important to recognize that the same cluster occurs at the other extreme of (young) age, and that respiratory limitations characterize both of these periods of life.
在怀孕期间，女性保持饮食中钙和铁的能力增加，婴儿似乎容易受到超负荷的影响。一个正常的婴儿在几个月内都不需要饮食中的铁，因为它使用了组织中储存的铁，最近有报道说正常的胎儿和婴儿可能有钙化的脑下垂体。结节有时可见垂体细胞死亡。(Groisman等)据推测，钙化在婴儿成长过程中被再吸收。这让人想起了在新生儿中发现的“年龄色素”，代表胎儿缺氧的压力，因为它在出生后不久就消失了。铁超载、老年性色素和软组织钙化是如此普遍地与老年有关，因此认识到同样的群集也发生在(年轻)年龄的另一个极端是很重要的，呼吸限制是这两个生命阶段的特征。
Calcium is probably the most popular element in physiological research, since it functions as a regulatory trigger in many cell processes, including cell stimulation and cell death. Its tendency to be deposited with iron in damaged tissue has often been mentioned. In hot weather, chickens pant to cool themselves, and this can lead to the production of thin egg shells. Carbonated water provides enough carbon dioxide to replace that lost in panting, and allows normal calcification of the shells. [Science 82, May, 1982] The deposition of calcium is the last phase of the “tertiary coat” of the egg, to which the oviduct glands successively add albumin, “egg membrane,” and the shell, containing matrix proteins (including some albumin; Hincke, 1995) and calcium crystals. Albumin is the best understood of these layers, but it is still complex and mysterious; its unusual affinity for metal ions has invited comparisons with proteins of the immune system. It is known to be able to bind iron strongly, and this is considered to have an “immunological” function, preventing the invasion of organisms that depend on iron. Maria de Sousa (“Iron and the lymphomyeloid system: A growing knowledge,” Iron in Immunity, Cancer and Inflammation, ed. by M. de Sousa and J. H. Brock, Wiley & Sons, 1989) has argued that the oxygen delivery system and the immune system evolved together, recycling iron in a tightly controlled system.
钙可能是生理学研究中最受欢迎的元素，因为它在许多细胞过程中起调节触发器的作用，包括细胞刺激和细胞死亡。它与铁沉积在受损组织中的倾向已被经常提及。在炎热的天气里，鸡会喘气来降温，这可能会导致蛋壳变薄。碳酸水提供了足够的二氧化碳来补充在喘气中失去的二氧化碳，并允许贝壳正常钙化。【科学82,1982年5月】钙的沉积是卵的“三级被膜”的最后阶段，输卵管腺体依次添加白蛋白、“卵膜”和蛋壳，其中含有基质蛋白(包括一些白蛋白;Hincke, 1995)和钙晶体。白蛋白是这些层中最了解的，但它仍然是复杂和神秘的;它对金属离子不同寻常的亲和力引起了人们对免疫系统蛋白质的比较。众所周知，它能够强烈地结合铁，这被认为有一种“免疫”功能，防止依赖铁的生物的入侵。玛丽亚·德索萨(Maria de Sousa，《铁和淋巴系统:不断增长的知识》，《免疫、癌症和炎症中的铁》，由M. de Sousa和J. H. Brock主编，Wiley Sons出版社，1989)认为，氧气输送系统和免疫系统一起进化，在一个严格控制的系统中循环利用铁。
The role of macrophages in the massive turnover of hemoglobin, and as osteoclasts, gives us a perspective in which iron and calcium are handled in analogous ways. Mechnikov's view of the immune system, growing from his observations of the “phagocytes,” similarly gave it a central role in the organism as a form-giving/ nutrition-related process. In a family with “marble-bone disease,” or osteopetrosis, it was found that their red blood cells lacked one form of the carbonic anhydrase enzyme, and that as a result, their body fluids retained abnormally high concentrations of carbon dioxide. Until these people were studied, it had been assumed that an excess of carbon dioxide would have the opposite effect, dissolving bones and causing osteoporosis or osteopenia, instead of osteopetrosis. The thyroid hormone is responsible for the carbon dioxide produced in respiration. Chronic hypothyroidism causes osteopenia, and in this connection, it is significant that women (as a result of estrogen's effects on the thyroid) are much more likely than men to be hypothyroid, and that, relative to men, women in general are “osteopenic,” that is, they have more delicate skeletons than men do.
巨噬细胞在血红蛋白的大量转化和破骨细胞中的作用，使我们对铁和钙的处理方式有了类似的认识。梅奇尼科夫对免疫系统的观点来自于他对“吞噬细胞”的观察，同样使免疫系统作为一种与形成/营养相关的过程，在有机体中扮演着核心角色。在一个患有“大理石骨病”或骨质硬化的家庭中，研究人员发现他们的红细胞缺乏一种碳酸酐酶，因此，他们的体液中二氧化碳浓度异常高。在对这些人进行研究之前，人们一直认为过量的二氧化碳会产生相反的效果，溶解骨骼，导致骨质疏松或骨质减少，而不是骨质硬化。甲状腺激素负责呼吸过程中产生的二氧化碳。慢性甲状腺功能减退导致骨量减少,在这一点上,它是重要的,女性(由于雌激素对甲状腺的影响)比男性更有可能是甲状腺,而且,相对于男性,女性一般”osteopenic”,也就是说,他们有比男性更纤细的骨骼。
In an experiment, rats were given a standard diet, to which had been added 1% Armour thyroid, that is, they were made extremely hyperthyroid. Since their diet was inadequate (later experiments showed that this amount of thyroid didn't cause growth retardation when liver was added to the diet) for their high metabolic rate, they died prematurely, in an apparently undernourished state, weighing much less than normal rats. Their bones, however, were larger and heavier than the bones of normal rats. A few incompetent medical “studies” have made people fear that “taking thyroid can cause osteoporosis.” Recognizing that hypothyroid women are likely to have small bones and excessive cortisol production, the inadequate treatment of hypothyroidism with thyroxin (the thyroid-suppressive precursor material), is likely to be associated with relative osteoporosis, simply because it doesn't correct hypothyroidism. Similar misinterpretations have led people to see an association between “thyroid use” (generally thyroxin) and breast cancer–hypothyroid women are likely to have cancer, osteoporosis, obesity, etc., and are also likely to have been inadequately treated for hypothyroidism. T3, the active form of thyroid hormone, does contribute to bone formation. (For example, M. Alini, et al.)
在一项实验中，老鼠被给予标准饮食，其中添加了1%的甲状甲状腺甲，也就是说，它们被制成了极度甲状甲状腺亢进。由于它们的饮食缺乏足够的代谢率(后来的实验表明，当饮食中加入肝脏时，这种数量的甲状腺不会导致生长迟缓)，它们在明显营养不良的状态下过早死亡，体重比正常大鼠轻得多。然而，它们的骨骼比正常老鼠的骨骼更大更重。一些不合格的医学“研究”让人们担心“服用甲状腺会导致骨质疏松症”。认识到甲状腺机能减退的女性很可能骨骼较小，皮质醇分泌过多，甲状腺素(甲状腺抑制前体物质)对甲状腺机能减退的治疗不充分，很可能与相对的骨质疏松症有关，因为它不能纠正甲状腺机能减退。类似的误解也让人们看到了“甲状腺使用”(通常是甲状腺素)和乳腺癌之间的联系——甲状腺机能减退的女性很可能患有癌症、骨质疏松症、肥胖症等，而且也可能因为甲状腺机能减退而没有得到适当的治疗。T3，甲状腺激素的活性形式，确实有助于骨形成。(例如，M. Alini等)
Around the same time (early 1940s) that the effects of thyroid on bone development were being demonstrated, progesterone was found to prevent age-related changes in bones, and “excessive” seeming doses of thyroid were found to prevent age-related joint diseases in rats.
大约在同一时间(20世纪40年代初)，甲状腺对骨骼发育的影响被证实，黄体酮被发现可以防止与年龄相关的骨骼变化，而“过量”的甲状腺似乎可以防止老鼠的年龄相关关节疾病。
A logical course of events, building on these and subsequent discoveries, would have been to observe that the glucocorticoids cause a negative calcium balance, leading to osteoporosis, and that thyroid and progesterone oppose those hormones, protecting against osteoporosis. But the drug industry had discovered the profits in estrogen (“the female hormone”) and the cortisone-class of drugs. Estrogen was promoted to prevent miscarriages, to stop girls (and boys) from growing too tall, to cure prostate and breast cancer, to remedy baldness, and 200 other absurdities. As all of those frauds gradually became untenable, even in the commercial medical culture, the estrogen industry began to concentrate on osteoporosis and femininity. Heart disease and Alzheimer's disease back those up.
基于这些和随后的发现，一个合乎逻辑的事件过程是，观察到糖皮质激素导致钙负平衡，导致骨质疏松症，甲状腺和孕酮对抗这些激素，防止骨质疏松症。但是制药业发现雌激素(“女性荷尔蒙”)和可的松类药物有利可图。雌激素被用来防止流产，防止女孩(和男孩)长得太高，治疗前列腺癌和乳腺癌，治疗脱发，以及其他200种荒谬的事情。随着所有这些欺诈行为逐渐站不住了，甚至在商业医疗文化中，雌激素行业开始专注于骨质疏松症和女性气质。心脏病和阿尔茨海默病也证实了这一点。
“If estrogen causes arthritis, prescribe prednisone for the inflammation. If prednisone causes osteoporosis, increase the dose of estrogen to retard the bone-loss. People are tough, and physiological therapies aren't very profitable.”
“如果雌激素导致关节炎，就用强的松来治疗炎症。如果强的松导致骨质疏松，增加雌激素的剂量以延缓骨质流失。人是坚强的，生理疗法也不是很赚钱。”
Fifteen years ago I noted in a newsletter that hip fractures most often occur in frail, underweight old women, and that heavier, more robust women seem to be able to bear more weight with less risk of fracture. Although I hadn't read it at the time, a 1980 article (Weiss, et al.) compared patients with a broken hip or arm with a control group made up of hospitalized orthopedic patients with problems other than hip or arm fractures. The fracture cases' weight averaged 19 pounds lighter than that of the other patients. They were more than 3.6 times as likely to be alcoholic or epileptic. It would be fair to describe them as a less robust group.
15年前，我在一份时事通讯中注意到，髋骨骨折最常发生在身体虚弱、体重过轻的老年妇女身上，而体重更重、更健壮的妇女似乎能够承受更大的体重，但骨折的风险更低。尽管我当时还没有读过，1980年的一篇文章(Weiss等人)将髋部或手臂骨折的患者与对照组进行了比较，对照组是由髋关节或手臂骨折以外的住院骨科患者组成。骨折患者的体重平均比其他患者轻19磅。他们酗酒或癫痫的可能性是正常人的3.6倍以上。将他们描述为一个不那么强大的群体是公平的。
Since the use of estrogen has become so common in the U.S., it is reasonable to ask whether the incidence of hip fractures in women over 70 has declined in recent decades. If estrogen protects against hip fractures, then we should see a large decrease in their incidence in the relevant population.
由于雌激素的使用在美国变得如此普遍，我们有理由问一下，在最近几十年里，70岁以上的女性髋部骨折的发生率是否有所下降。如果雌激素能预防髋部骨折，那么我们应该能看到相关人群中髋部骨折的发生率大幅下降。
Hip fractures, like cancer, strokes, and heart disease, are strongly associated with old age. Because of the baby-boom, 1945 to 1960, our population has a bulge, a disproportion in people between the ages of 35 and 50, and those older. Increasingly, we will be exposed to publicity about the declining incidence of disease, fraudulently derived from the actually declining proportion of old people. For example, analyzing claims based on the pretense that the population bulge doesn't exist, I have seen great publicity given to studies that would imply that our life-expectancy is now 100 years, or more.
髋部骨折，如癌症、中风和心脏病，与老年密切相关。由于1945年至1960年的婴儿潮，我们的人口出现了膨胀，35岁至50岁之间的人和年龄更大的人比例失调。我们将越来越多地接触到有关疾病发病率下降的宣传，这些宣传欺骗性地源自老年人实际比例的下降。例如，在分析以人口膨胀不存在为借口的断言时，我发现那些暗示我们现在的预期寿命是100岁甚至更多的研究得到了极大的宣传。
Comparing the number of hip fractures, per 1000 75 year old women, in 1996, with the rate in 1950, we would have a basis for judging whether estrogen is having the effect claimed for it.
将1996年每1000名75岁老年妇女的髋部骨折数量与1950年的比率进行比较，我们就有了一个判断雌激素是否具有所宣称的效果的基础。
The x-ray data seem to convince many people estrogen is improving bone health, by comparing measurements in the same person before and after treatment. Does estrogen cause water retention? Yes. Does tissue water content increase measured bone density? Yes. Are patients informed that their “bone scans” don't have a scientific basis? No. The calcification of soft tissues under the influence of estrogen must also be taken into account in interpreting x-ray evidence. (Hoshino, 1996) Granted that woman who are overweight have fewer hip fractures (and more cancer and diabetes), what factors are involved? Insulin is the main factor promoting fat storage, and it is anabolic for bone. (Rude and Singer, “Hormonal modifiers of mineral metabolism.”) The greatest decrease in bone mass resulting from insulin deficiency was seen in white females, and after five years of insulin treatment, there was a lower incidence of decreased bone mass (Rosenbloom, et al., 1977). McNair, et al. (1978 and 1979) found that the loss of bone mass coincided with the onset of clinical diabetes. Since excess cortisol can cause both high blood sugar and bone loss, when diabetes is defined on the basis of high blood sugar, it will often involve high blood sugar caused by excess cortisol, and there will be calcium loss. Elsewhere, I have pointed out some of the similarities between menopause and Cushing's syndrome; a deficiency of thyroid and progesterone can account for many of these changes. Nencioni and Polvani have observed the onset of progesterone deficiency coinciding with bone loss, and have emphasized the importance of progesterone's antagonism to cortisol.
通过比较同一个人在治疗前后的测量数据，x射线数据似乎说服了许多人雌激素正在改善骨骼健康。雌激素会导致水潴留吗?是的。组织含水量会增加测量到的骨密度吗?是的。患者是否被告知他们的“骨扫描”没有科学依据?不。在解释x线证据时，也必须考虑到雌激素影响下的软组织钙化。(Hoshino, 1996)就算超重的女性髋骨骨折更少(癌症和糖尿病更多)，其中涉及哪些因素?胰岛素是促进脂肪储存的主要因素，它是骨骼的合成代谢。(Rude和Singer，“矿物质代谢的激素调节剂”)胰岛素缺乏导致的骨量下降最大的是白人女性，胰岛素治疗5年后，骨量下降的发生率较低(Rosenbloom, et al.， 1977)。McNair等人(1978和1979)发现骨量的减少与临床糖尿病的发病相一致。由于皮质醇过多会导致高血糖和骨质流失，当糖尿病以高血糖为基础定义时，往往会涉及皮质醇过多引起的高血糖，同时还会出现钙流失。在其他地方，我已经指出了更年期和库欣综合征之间的一些相似之处;甲状腺和黄体酮的缺乏可以解释许多这些变化。Nencioni和Polvani观察到孕酮缺乏与骨丢失同时发生，并强调孕酮对抗皮质醇的重要性。
Johnston (1979) found that progesterone (but not estrone, estradiol, testosterone, or androstenedione) was significantly lower in those losing bone mass most rapidly.
约翰斯顿(1979)发现，在那些骨量流失最快的人群中，孕酮(而不是雌二醇、雌二醇、睾酮或雄烯二酮)明显较低。
Around the age of 50, when bone loss is increasing, progesterone and thyroid are likely to be deficient, and cortisol and prolactin are likely to be increased. Prolactin contributes directly to bone loss, and is likely to be one of the factors that contributes to decreased progesterone production.
在50岁左右，骨质流失加剧，孕酮和甲状腺可能会不足，皮质醇和催乳素可能会增加。催乳素直接导致骨质流失，很可能是导致孕酮分泌减少的因素之一。
Estrogen tends to cause increased secretion of prolactin and the glucocorticoids, which cause bone loss, but it also promotes insulin secretion, which tends to prevent bone loss. All of these factors are associated with increased cancer risk.
雌激素会增加催乳素和糖皮质激素的分泌，导致骨质流失，但它也会促进胰岛素的分泌，从而防止骨质流失。所有这些因素都与癌症风险增加有关。
Thyroid and progesterone, unlike estrogen, stimulate bone-building, and are associated with a decreased risk of cancer. It seems sensible to use thyroid and progesterone for their general anti-degenerative effects, protecting the bones, joints, brain, immune system, heart, blood vessels, breasts, etc.
与雌激素不同的是，甲状腺和黄体酮能刺激骨骼形成，并能降低患癌症的风险。使用甲状腺和黄体酮似乎是明智的，因为它们具有抗退化的作用，可以保护骨骼、关节、大脑、免疫系统、心脏、血管、乳房等。
But the issue of calcification/decalcification is so general, we mustn't lose interest just because the practical problem of osteoporosis is approaching solution.
但钙化/脱钙的问题是如此普遍，我们不能因为骨质疏松症的实际问题即将得到解决而失去兴趣。
For example, healthy high energy metabolism requires the exclusion of most calcium from cells, and when calcium enters the stimulated or deenergized cell, it is likely to trigger a series of reactions that lower energy production, interfering with oxidative metabolism. During aging, both calcium and iron tend to accumulate and they both seem to have an affinity for similar locations, and they both tend to displace copper. (Compare K. Sato, et al., on the calcification of copper-containing paints.) Elastin is a protein, the units of which are probably bound together by copper atoms. In old age, elastin is one of the first substances to calcify, for example in the elastic layers of arteries, causing them to lose elasticity, and to harden into almost bone-like tubes. In the heart and kidneys, the mitochondria (rich in copper-enzymes) are often the location showing the earliest calcification, for example when magnesium is deficient.
例如，健康的高能量代谢需要从细胞中排除大部分的钙，当钙进入受刺激或失能的细胞时，很可能会触发一系列降低能量产生的反应，干扰氧化代谢。在衰老过程中，钙和铁都倾向于积累它们似乎都对相似的位置有亲和力，它们都倾向于取代铜。(比较K. Sato等人对含铜涂料钙化的研究。)弹性蛋白是一种蛋白质，其单位可能是由铜原子结合在一起的。在老年，弹性蛋白是最早钙化的物质之一，例如在动脉的弹性层中，导致动脉失去弹性，硬化成骨状的管状。在心脏和肾脏中，线粒体(富含铜酶)通常是最早出现钙化的部位，例如缺镁时。
Obviously, certain proteins have higher than average affinity for copper, iron, and calcium. For example, egg-white's unusual behavior with copper can be seen if you make a meringue in a copper pan–the froth is unusually firm. My guess is that copper atoms bind the protein molecules into relatively elastic systems. In many systems, calcium forms the link between adhesive proteins.
显然，某些蛋白质对铜、铁和钙的亲和力高于平均亲和力。例如，如果你用铜锅做蛋白霜，可以看到蛋白与铜的不同寻常的行为——泡沫异常坚硬。我猜是铜原子将蛋白质分子结合成相对有弹性的系统。在许多系统中，钙形成粘附蛋白之间的连接。
In brain degeneration, the regions that sometimes accumulate aluminum, will accumulate other metals instead, if they predominate in the environment; calcium is found in this part of the brain in some of the Pacific regions studied by Gajdusek. Certain cells in the brain used to be called “metalophils,” because they could be stained intensely with silver and other metals; I suppose these are part of the immune system, handling iron as described by Maria de Sousa. Macrophages have been proposed as an important factor in producing atherosclerotic plaques (Carpenter, et al.). There is evidence that they (and not smooth muscle cells) are the characteristic foam cells, and their conversion of polyunsaturated oils into age pigment accounts for the depletion of those fats in the plaques. The same evidence could be interpreted as a defensive reaction, binding iron and destroying unsaturated fatty acids, and by this detoxifying action, possibly protecting against calcification and destruction of elastin. (This isn't the first suggestion that atherosclerosis might represent a protective process; see S. M. Plotnikov, et al., 1994.)
在大脑退化过程中，有时积聚铝的区域会积聚其他金属，如果它们在环境中占主导地位;在Gajdusek研究的太平洋区域的大脑中发现了钙。大脑中的某些细胞过去被称为“嗜金属细胞”，因为它们可以被银和其他金属强烈染色;我想这是免疫系统的一部分，像Maria de Sousa描述的那样处理铁。巨噬细胞被认为是产生动脉粥样硬化斑块的重要因素(Carpenter等)。有证据表明，它们(而不是平滑肌细胞)是典型的泡沫细胞，它们将多不饱和油脂转化为年龄色素是斑块中脂肪消耗的原因。同样的证据可以解释为防御反应，结合铁和破坏不饱和脂肪酸，并通过这种解毒作用，可能保护钙化和破坏弹性蛋白。(这并不是动脉粥样硬化可能代表一种保护过程的第一个建议;参见S. M. Plotnikov等人，1994。)
Since carbon dioxide and bicarbonate are formed in the mitochondria, it is reasonable to suppose that the steady outward flow of the bicarbonate anion would facilitate the elimination of calcium from the mitochondria. Since damaged mitochondria are known to start the process of pathological calcification in the heart and kidneys, it probably occurs in other tissues that are respiratorily stressed. And if healthy respiration, producing carbon dioxide, is needed to keep calcium outside the cell, an efficient defense system could also facilitate the deposition of calcium in suitable places–depending on specific protein binding. The over-grown bones in the hyperthyroid rats and the women with osteopetrosis suggest that an abundance of carbon dioxide facilitates bone formation. Since no ordinary inorganic process of precipitation/crystallization has been identified that could account for this, we should consider the possibility that the protein matrix is regulated in a way that promotes (or resists) calcification. The affinity of carbon dioxide for the amine groups on proteins (as in the formation of carbamino hemoglobin, which changes the shape of the protein) could change the affinity of collagen or other proteins for calcium. Normally, ATP is considered to be the most important substance governing such changes of protein conformation or binding properties, but ordinarily, ATP and CO2 are closely associated, because both are produced in respiration. Gilbert Ling has suggested that hormones such as progesterone also act as cardinal adsorbants, regulating the affinity of proteins for salts and other molecules.
由于二氧化碳和碳酸氢盐是在线粒体中形成的，因此有理由假设，碳酸氢盐负离子的稳定向外流动将促进线粒体中钙的消除。由于已知受损的线粒体会启动心脏和肾脏的病理性钙化过程，它可能会发生在其他有呼吸压力的组织中。如果健康的呼吸(产生二氧化碳)需要将钙保持在细胞外，一个有效的防御系统也可以促进钙在合适的地方沉积——这取决于特定的蛋白质结合。甲状腺机能亢进的大鼠和患有骨质硬化的妇女的骨骼过度生长表明，大量的二氧化碳有助于骨骼形成。由于没有发现可以解释这一现象的普通无机沉淀/结晶过程，我们应该考虑蛋白质基质以促进(或抵抗)钙化的方式被调节的可能性。二氧化碳对蛋白质上胺基的亲和性(如在碳氨基血红蛋白的形成过程中，它改变了蛋白质的形状)可以改变胶原蛋白或其他蛋白质对钙的亲和性。通常，ATP被认为是控制蛋白质构象或结合特性变化的最重要的物质，但通常，ATP和CO2是密切相关的，因为两者都是在呼吸过程中产生的。Gilbert Ling认为，孕酮等激素也起到主要吸附剂的作用，调节蛋白质对盐和其他分子的亲和力。
Cells have many proteins with variable affinity for calcium; for example in muscle, a system called the endoplasmic reticulum, releases and then sequesters calcium to control contraction and relaxation. (This calcium-binding system is backed up by–and is spatially in close association with–that of the mitochondrion.) Ion-exchange resins can be chemically modified to change their affinity for specific ions, and molecules capable of reacting strongly with proteins can change the affinities of the proteins for minerals. What evidence is there that carbon dioxide could influence calcium binding? The earliest deposition of crystals on implanted material is calcium carbonate. (J. Vuola, et al, 1996.) In newly formed bone, the phosphate content is low, and increases with maturity. While mature bone has an apatite-like ratio of calcium and phosphate, newly calcified bone is very deficient in phosphate (according to Dallemagne, the initial calcium to phosphorus ratio is 1.29, and it increases to 2.20.) (G. Bourne, 1972; Dallemagne.)
细胞中有许多对钙具有不同亲和力的蛋白质;例如，在肌肉中，有一个叫做内质网的系统，释放并隔离钙以控制收缩和放松。(这个钙结合系统是由线粒体支持的，并且在空间上与线粒体密切相关。)离子交换树脂可以通过化学改性来改变其对特定离子的亲和性，而能够与蛋白质发生强烈反应的分子可以改变蛋白质对矿物质的亲和性。有什么证据表明二氧化碳会影响钙的结合?晶体在植入材料上最早的沉积是碳酸钙。(J. Vuola等，1996。)在新形成的骨中，磷酸盐含量较低，随着成熟度的增加而增加。虽然成熟的骨具有磷灰石样的钙和磷酸盐的比例，但新钙化的骨非常缺乏磷酸盐(根据达勒曼，最初的钙磷比是1.29，它增加到2.20)(G. Bourne, 1972;Dallemagne)。
The carbonate content of bone is often ignored, but in newly formed bone, it is probably the pioneer. Normally, “nucleation” of crystals is thought of as a physical event in a supersaturated solution, but the chemical interaction between carbon dioxide and amino groups (amino acids, protein, or ammonia, for example) removes the carbon dioxide from solution, and the carbamino acid formed becomes a bound anion with which calcium can form a salt. With normal physiological buffering, the divalent calcium (Ca2+) should form a link between the monovalent carbamino acid and another anion. Linking with carbonate (CO32-), one valence would be free to continue the salt-chain. This sort of chemistry is compatible with the known conditions of bone formation.
骨骼的碳酸盐含量往往被忽视，但在新形成的骨骼中，它可能是先驱者。通常情况下,晶体的成核被认为是一个物理事件在过饱和溶液,但二氧化碳之间的化学作用和氨基酸组(氨基酸、蛋白质、氨)消除了二氧化碳解决方案,和氨基甲酸的酸形成成为绑定可以形成钙盐的阴离子。在正常的生理缓冲作用下，二价钙(Ca2+)应该在一价氨基酸和另一个阴离子之间形成连接。与碳酸盐(CO32-)连接，一价就可以自由地继续盐链。这种化学反应与已知的骨形成条件是一致的。
Klein, et al. (1996), think of uncoupled oxidative phosphorylation in terms of “subtle thermogenesis,” which isn't demonstrated in their experiment, but their experiment actually suggests that stimulated production of carbon dioxide is the factor that stimulates calcification. Their experiment seems to be the in vitro equivalent of the various observations mentioned above. DHEA, which powerfully stimulates bone formation, is (like thyroid and progesterone) thermogenic, but in these cases, the relevant event is probably the stimulation of respiration, not the heat production. In pigs (Landrace strain) susceptible to malignant hyperthermia, there is slow removal of calcium from the contractile apparatus of their muscles. Recent evidence shows that an extramitochondrial NADH-oxidase is functioning. This indicates that carbon dioxide production is limited. I think this is responsible for the cells' sluggishness in expelling calcium.
Klein等人(1996)，从“微妙的生热作用”的角度考虑不耦合氧化磷酸化，这在他们的实验中没有证实，但他们的实验实际上表明，刺激二氧化碳的产生是刺激钙化的因素。他们的实验似乎是上述各种观察的体外等效物。脱氢表雄酮(DHEA)能强烈刺激骨骼形成，(像甲状腺和黄体酮一样)产热，但在这些情况下，相关的事件可能是呼吸的刺激，而不是产热。在猪(长白猪)易感恶性热疗，有缓慢的钙从他们的肌肉收缩装置。最近的证据表明，线粒体外nadh氧化酶在起作用。这表明二氧化碳的产生是有限的。我认为这是细胞缓慢排出钙的原因。
Stress-susceptible pigs show abnormalities of muscle metabolism (e.g., high lactate formation) that are consistent with hypothyroidism. (T. E. Nelson, et al., “Porcine malignant hyperthermia: Observations on the occurrence of pale, soft, exudative musculature among susceptible pigs,” Am. J. Vet. Res. 35, 347-350, 1974; M. D. Judge, et al., “Adrenal and thyroid function in stress-susceptible pigs (Sus domesticus),” Am. J. Physiol. 214(1), 146-151, 1968.)
应激易感猪表现出肌肉代谢异常(例如，高乳酸形成)，与甲状腺功能减退一致。(T. E. Nelson等，“猪恶性热疗:对易感猪中苍白、柔软、渗出性肌肉组织发生的观察”，美国;j .兽医。第35、347- 350,1974号决议;m.d. Judge等，“应激易感猪(Sus domesticus)的肾上腺和甲状腺功能”，美国。中国科学(d辑:生命科学)
Malignant hyperthermia during surgery is usually blamed on genetic susceptibility and sensitivity to anesthetics. (R. D. Wilson, et al., “Malignant hyperpyrexia with anesthesia,” JAMA 202, 183-186, 1967; B.A Britt and W. Kalow, “Malignant hyperthermia: aetiology unknown,” Canad. Anaesth. Soc. J. 17, 316-330, 1970.) Hypertonicity of muscles, various degrees of myopathy and rigidity, and uncoupling of oxidative phosphorylation occur in these people, as in pigs. Lactic acidosis suggests that mitochondrial respiration is defective in the people, as in the pigs. Besides the sensitivity to anesthetics, the muscles of these people are abnormally sensitive to caffeine and elevated extracellular potassium. During surgery, artificial ventilation, combined with stress, toxic anesthetics, and any extramitochondrial oxidation that might be occurring (such as NADH-oxidase, which produces no CO2), make relative hyperventilation a plausible explanation for the development of hyperthermia. Hyperventilation can cause muscle contraction. Panting causes a tendency for fingers and toes to cramp. Free intracellular calcium is the trigger for muscle contraction (and magnesium is an important factor in relaxation.) Capillary tone, similarly, is increased by hyperventilation, and relaxed by carbon dioxide. The muscle-relaxing effect of carbon dioxide shows that the binding of intracellular calcium is promoted by carbon dioxide, as well as by ATP. The binding of calcium in a way that makes it unable to interfere with cellular metabolism is, in a sense, a variant of simple extrusion of calcium, and the binding of calcium to extracellular materials. A relaxed muscle and a strong bone are characterized by bound calcium.
手术过程中的恶性热疗通常被归咎于遗传易感性和对麻醉剂的敏感性。(R. D. Wilson等人，“麻醉下的恶性高热”，JAMA 202, 183- 186,1967;B.A Britt和W. Kalow，“恶性热疗:病因不明”，加拿大。Anaesth。Soc。J. 17, 316- 330,1970。像猪一样，这些人出现肌肉高张力、不同程度的肌病和强直以及氧化磷酸化的解耦。乳酸酸中毒表明人和猪一样，线粒体呼吸有缺陷。除了对麻醉剂敏感外，这些人的肌肉对咖啡因和升高的细胞外钾也异常敏感。在手术过程中，人工通气、压力、有毒麻醉剂和任何可能发生的线粒体外氧化(如nadh -氧化酶，它不产生二氧化碳)使相对过度通气成为热疗发展的合理解释。过度换气会引起肌肉收缩。喘气会导致手指和脚趾抽筋。细胞内游离钙是肌肉收缩的触发器(镁是放松的重要因素)。同样，过度换气会增加毛细血管张力，二氧化碳会使毛细血管松弛。二氧化碳的肌肉松弛作用表明，二氧化碳和ATP促进了细胞内钙的结合。在某种意义上，钙的结合使其无法干扰细胞代谢，这是简单的钙挤压的一种变体，钙与细胞外物质的结合。松弛的肌肉和强壮的骨骼的特征是结合钙。
Activation of the sympathetic nervous system promotes hyperventilation. This means that hypothyroidism, with high adrenalin (resulting from a tendency toward hypoglycemia because of inefficient use of glucose and oxygen), predisposes to hyperventilation.
交感神经系统的激活促进过度通气。这意味着甲状腺功能减退，伴随着高肾上腺素(由于葡萄糖和氧气的低效使用导致低血糖倾向)，容易导致过度通气。
Muscle stiffness, muscle soreness and weakness, and osteoporosis all seem to be consequences of inadequate respiration, allowing lactic acid to be produced instead of carbon dioxide. Insomnia, hyperactivity, anxiety, and many chronic brain conditions also show evidence of defective respiration, for example, either slow consumption of glucose or the formation of lactic acid, both of which are common consequences of low thyroid function. Several studies (e.g., Jacono and Robertson, 1987) suggest that abnormal calcium regulation is involved in epilepsy. The combination of supplements of thyroid (emphasizing T3), magnesium, progesterone and pregnenolone can usually restore normal respiration, and it seems clear that this should normalize calcium metabolism, decreasing the calcification of soft tissues, increasing the calcification of bones, and improving the efficiency of muscles and nerves. (Magnesium, like carbonate, is a component of newly formed bone.) The avoidance of polyunsaturated vegetable oils is important for protecting respiration; some of the prostaglandins they produce have been implicated in osteoporosis, but more generally, they antagonize thyroid function and they can interfere with calcium control. The presence of the “Mead acid” (the omega-9 unsaturated fat our enzymes synthesize) in cartilage suggests a new line of investigation regarding the bone-toxicity of the polyunsaturated dietary oils.
肌肉僵硬、肌肉酸痛无力和骨质疏松症似乎都是呼吸不足的后果，导致乳酸而不是二氧化碳的产生。失眠、多动、焦虑和许多慢性脑部疾病也显示出呼吸缺陷的证据，例如，葡萄糖消耗缓慢或乳酸形成，这两种情况都是甲状腺功能低下的常见后果。一些研究(例如，Jacono和Robertson, 1987)表明，异常的钙调节与癫痫有关。甲状腺(强调T3)、镁、孕酮和孕烯醇酮的补充通常可以恢复正常的呼吸，显然这应该使钙代谢正常化，减少软组织的钙化，增加骨骼的钙化，并提高肌肉和神经的效率。(镁，像碳酸盐一样，是新形成的骨骼的组成部分。)避免食用多不饱和植物油对保护呼吸很重要;它们产生的一些前列腺素与骨质疏松症有关，但更普遍的是，它们会对抗甲状腺功能并干扰钙的控制。软骨中存在的“米德酸”(我们的酶合成的-9不饱和脂肪)提示了关于多不饱和饮食油的骨骼毒性的新研究方向。
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“退行性脊柱和主动脉钙化对绝经后妇女骨密度测量的影响:骨质疏松症与心血管疾病之间的联系?”欧元。中国的j。调查24(12)，813-817,1994。(“通过双光子吸收仪测量，患有脊柱退行性钙化的女性与没有钙化的女性相比，脊柱骨密度更高。”“与无主动脉钙化的女性相比，主动脉钙化女性的定量计算机断层扫描和股骨近端骨密度显著降低。”
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P. Schneider和C. Reiners, JAMA 277(1)， 1997年1月1日23日。双能x射线骨密度吸收仪可能导致对骨矿物质含量的错误结论，因为组织脂肪或水含量的改变。“用DEXA测量骨量时，脂肪分布的影响是相当大的，误差范围高达每2厘米脂肪10%。”
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杰。患有和不患有主动脉粥样硬化的女性的维生素K状况和骨量:一项基于人群的研究。实习医师。59(5)，352-356,1996。(“在患有动脉粥样硬化的女性中，维生素K状况与骨量有关，这一发现支持了我们的假设，即维生素K状况影响骨骼和动脉粥样硬化斑块中的矿化过程。”
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M. Alini等，“在无血清培养中，甲状腺激素可诱导软骨细胞肥大的充分表达导致基质钙化”，J. of Bone and Mineral Res. 11(1)， 105-113, 1996。(“…比较了T3和T4对三种细胞肥大表型和基质钙化的刺激能力。prehypertrophic软骨细胞亚群”。＂…T3至少是T4的50倍。T3的作用在最不成熟的细胞中最为明显。”＂…通过在细胞层中加入Ca45(2+)来测量基质钙化，与T4培养相比，T3培养的细胞通常更早发生基质钙化。”
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