Bone is the main depository of calcium. Fully 99 percent of the body’s calcium is in the skeleton, with the rest in extracellular fluid and soft tissues. As early as the sixteenth century, it was recognized by a Dutch physician that the skeleton is not an inactive but a dynamic tissue under hormonal influence and capable of remodeling throughout life (Lutwak, Singer, and Urist 1974). Two specific types of bone cells acted upon in these processes are the osteoblasts (involved in bone formation) and the osteoclasts (involved in bone resorption).
Another important discovery in the history of calcium was made by Sidney Ringer more than 100 years ago. He demonstrated that the contractility of cardiac muscle was stimulated and maintained by the addition of calcium to the perfusion fluid (Ringer 1883). It has also been shown that this important effect of calcium is not limited to cardiac muscle but has a generalized, activating effect in practically all differentiated cells (Opie 1980; Rubin 1982; Campbell 1986). However, in addition to calcium, the presence of specific concentrations of sodium and potassium are needed to achieve this effect (Mines 1911; Lowen-stein and Rose 1978).
The state of calcium in the body investigated many decades ago has been subsequently summarized (“The Classic” 1970). The amount of calcium in the body is greater than that of any other positively charged mineral (1,160 grams [g]). Its place of storage is the skeleton, although the small amounts present in the compartments of the extracellular fluid and those of the soft tissues are of great physiological importance because the calcium stored in bone maintains equilibrium with other calcium pools in the body (Rubin 1982).
The interaction and balance of vitamin D, calcitonin, and parathyroid hormone (PTH) are the pillars of normal calcium metabolism, and they play an important role in maintaining a highly controlled calcium homeostasis and normal serum calcium level. This process is based on the direct or indirect action of these substances on the skeleton. Vitamin D is produced by ultraviolet radiation of sunlight on the skin, which yields the vitamin D precursor ergosterol (Hess and Weinstock 1924). The hormones calcitonin and PTH are created, respectively, by the C cells of the thyroid gland and by the parathyroid glands. A deficiency as well as an excessive production and secretion of these three substances can lead to the development of specific disease states.
Vita'mi-n D
Vitamin D, discovered at the beginning of the third decade of the twentieth century, is the substance that acts to prevent rickets. Many of the original reports of the discovery of vitamin D have been republished (Robertson 1969; Pramanik, Gupta, and Agarwal 1971) and are cited here for those who wish to consult them. In addition, the early discovery of the physiological importance of calcium (Ringer 1883) has been redescribed (Fye 1984; Ebashi 1987). The chemical structure of vitamin D was identified by a German chemist, Adolf Windaus, in 1931,and the subsequent commercial production of vitamin D practically eliminated the occurrence of rickets - the vitamin D deficiency disease of children - although treatment with cod-liver oil (rich in vitamin D) also played an important role in the eradication of this disease.
Even though our basic knowledge of vitamin D was obtained between 1919 and 1924, it was not until the 1960s that the vitamin D metabolites were discovered (Lund and DeLuca 1966; Ponchon and DeLuca 1969; Olson, Jr., and DeLuca 1973; DeLuca 1979, 1980, 1988). H. F DeLuca postulated that vitamin D must be hydroxylated first in the liver and subsequently by 1-alpha-hydroxylation in the kidney to produce the vitamin D hormone 1-alpha-25-dihy-droxyvitamin D3,1,25(OH)2D3. This is the important vitamin D metabolite that actively affects the absorption of calcium from the intestine. Further studies regarding the mechanism of calcium absorption from the intestine are credited to R. H. Wasserman, who discovered the vitamin D-dependent “calcium binding protein” (CaBP) in the duodenum (Kallfelz, Taylor, and Wasserman 1967; Wasserman, Corradina, and Taylor 1968; Wasserman and Taylor 1968).
Rickets, caused by vitamin D deficiency, was produced experimentally in the 1920s, and much was learned about this illness, which occurs in infancy and childhood at ages of rapid growth (Sherman and Pappenheimer 1921; Steenbock and Black 1924; Petti-for et al. 1978; Pettifor and Ross 1983). Rickets was common in the early part of the twentieth century, and more than 100 years ago it was recognized that a lack of sunlight was responsible, particularly in northern latitudes, where deprivation is most likely to occur. It was also noted that sunlight is curative (Palm 1890;Huldschinsky 1919;Mellanby 1921).
Symptoms of rickets include impaired calcification and excess formation of cartilage in areas of bone growth. The adult form of the disease is called osteomalacia, in which newly formed osteoid does not calcify. This occurs in persons who voluntarily or for other reasons are homebound and therefore not exposed to sunlight.
Several early investigators stated that both rickets and osteomalacia can also be caused by a nutritional deficiency of calcium (McCollum et al. 1921;Theiler 1976; McCollum et al. 1995). Although such a situation would be uncommon, it is possible that the theory was proposed because healing of rickets occurred when a low, insufficient calcium intake of barely more than 100 milligrams (mg)/day was raised to 1,200 mg/day with the simultaneous use of vitamin D. More recent investigators believed it unlikely that vitamin D deficiency alone could produce rickets or osteomalacia but that these diseases occur when there is coexistent calcium deficiency (Pettifor et al. 1981).
Calcitonin
The hormone calcitonin was discovered in 1962 by Harold Copp, who reported that it originates in the parathyroid glands (Copp et al. 1962; Copp 1967, 1969). Calcitonin decreases the calcium level in blood, and this effect was ascribed to decreased bone resorption. The first report of the use of calcitonin in humans came shortly after its discovery (Foster et al. 1966), and further studies revealed that this hormone actually originates in the C cells of the thyroid gland - which, for a while, gave rise to the use of the name “thyrocalcitonin” (Hirsch and Munson 1969). It has been shown experimentally that calcitonin affects not only bone resorption but also bone formation (Baylink, Morey, and Rich 1969).
Because of the ability of calcitonin to cause a decrease in bone resorption, it has been utilized in the treatment of patients with Paget’s disease - a deforming and frequently disabling bone disease diagnosed in England more than a century ago (Paget 1877; Bijvoet, Van der Sluys Veer, and Jansen 1968; Shai, Baker, and Wallach 1971; Woodhouse Bordier, et al. 1971). Two available types of calcitonin, primarily salmon calcitonin but also porcine calcitonin, have been joined by human calcitonin. All three types have been (and still are) used in investigative studies of their comparative effectiveness in treating Paget’s disease.
Parathyroid Hormone
Parathyroid hormone (PTH), discovered in the early 1920s (Collip 1925), consists of four small pea-sized structures, two of which are located on the upper pole and two at the lower pole of each thyroid lobe. When parathyroid glands, which produce PTH, are functioning normally, the level of secretion depends on the serum calcium level, which in turn depends, in part, on the fraction of the dietary calcium that is absorbed from the intestine and the amount of calcium released from the skeleton by bone resorp-tion. The dietary contribution of calcium to the serum calcium level influences the extent of bone resorption that is induced by PTH to maintain the well-controlled homeostasis of the normal serum calcium level.
The most common clinical aberration of calcium metabolism in hyperparathyroidism is a high level of serum calcium, a low level of serum phosphorus, and frequently, but not invariably, elevated levels of the serum enzyme alkaline phosphatase. There may also be evidence of bone loss on roentgenograms (which can mimic osteopenia) and, more rarely, cystic bone lesions. Kidney stone formation and peptic ulcer of the stomach may also result.
When there is hyperfunction of any of the four parathyroid glands, and excess PTH is secreted, a pathological condition develops that is called primary hyperparathyroidism. This endocrine disorder that affects bone metabolism (primarily the metabolism of calcium and phosphorus) was discovered in the early 1920s in Vienna and discussed in print two years later (Mandl 1926). In 1925, the condition was observed in the United States (Hannon et al. 1930), and shortly after, the first series of patients with hyperparathyroidism in the United States was described (Albright, Aub, and Bauer 1934). A classic study of the parathyroid glands followed in the late 1940s (Albright and Reifenstein 1948).
The symptoms and the treatment of hyperparathyroidism have been extensively discussed in older medical textbooks, which state, as did the classic article by F Albright, J. C. Aub, and W. Bauer in 1934, that the cause of primary hyperparathyroidism is the enlargement of one or more of the parathyroid glands to form a benign tumor (an adenoma) or a multiple adenomata. However, we now know that the adenoma of a single parathyroid gland or multiple adenomata of the parathyroid glands are the result of hyperfunction of the parathyroid glands - the increased secretion of PTH. The conventional treatment for primary hyperparathyroidism is the surgical removal of the enlarged parathyroid gland or glands.
Reports in the literature also attest to the importance of the role of vitamin D in normal parathyroid function (Mawer et al. 1975).There are also reports of vitamin D deficiency in hyperparathyroidism (Wood-house, Doyle, and Joplin 1971; Lumb and Stanbury 1974; Mawer et al. 1975; Stanbury 1981), and the use of vitamin D has been recommended for the medical treatment of patients with primary hyperparathyroidism (Woodhouse et al. 1973).
World History
