POSTGRAD. MED. J. (1964), 40, 497 Postgrad Med J: first published as 10.1136/pgmj.40.466.497 on 1 August 1964. Downloaded from INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS MICHAEL T. HARRISON, M.D., M.R.C.P. Lecturer in Medicine, University of Glasgow. From ihe Gardiner Institute of Medicine, Western Infirmary, Glasgow. IN man and most mammals the concentration and showed that reciprocal changes in con- of calcium in the blood and body fluids remains centration of calcium in the systemic circula- almost constant under normal conditions, with tion resulted. The mechanism by which the only slight fluctuations. For the various cellular parathyroid glands regulate their secretion in functions which are dependent on calcium, for response to changing levels of serum calcium example neuromuscular transmission, it is the is quite unknown. ionized fraction of calcium (approximately The parathyroid hormone has been puri- 50 per cent of the total serum calcium level) fied from bovine glands, and its properties which is important, and it is this fraction which have been studied (Rasmussen and Craig is so carefully maintained at a constant level 1961, 1962). It is a protein of molecular weight in the body fluids. In order to stabilize this approximately 9,000, composed of a single level, an elaborate regulating mechanism is chain containing 76 to 83 amino-acid residues. necessary, since there are many routes of entry It is antigenically pure, and antibodies have Protected by copyright. into and exit from the blood available to been prepared to it which provide the basis calcium. Thus, calcium is added to the blood for a sensitive immunoassay (Berson, Yalow, by absorption from the intestine and by resorp- Aurbach and Potts, 1963; Tashjian, Levine tion from bone, and leaves via formation of new and Munson, 1963). The most striking action bone, and by excretion into urine, fweces, sweat of the hormone is that on the skeleton, which and milk. Changes in other components of the results in release of calcium into the blood. body fluids, protein, citrate and phosphate, There is abundant evidence for this direct action affect the concentration of ionized calcium. of parathyroid hormone on bone, which has The magnitude of all these factors will vary been reviewed by Munson (1960), and strength- in response to growth, dietary intake, changes ened by the striking experiments of Gaillard in activity, or pregnancy, and yet the net effect (1961), who demonstrated resorption of bone on concentration of ionized calcium is almost in tissue culture in response to the hormone. undetectable. Two factors of major importance The mechanism by which parathyroid hormone http://pmj.bmj.com/ in the regulation of serum levels of calcium increases resorption of bone is not known. The are the parathyroid glands and vitamin D, and solubility of bone depends on pH of the sur- both of these are necessary to maintain normal rounding fluid; as pH falls solubility increases, levels. so that bone is resorbed. A possible mechanism for the action of parathyroid hormone on bone Parathyroid Glands would therefore be through a lowering of pH of If the parathyroid glands are removed, calcium the fluid immediately in contact with the bone. in the serum falls rapidly to a level at which This is the basis of the "acid theory" of action on September 24, 2021 by guest. increased neuromuscular irritability occurs, with of parathyroid hormone (Neuman, Firschein, the syndrome of tetany. The parathyroid Chen, Mulryan and DiStefano, 1956; Firschein, hormone raises the level of serum calcium, and Neuman, Martin and Mulryan 1959). These a fall in this level is the principal stimulus to the workers showed that the concentration of secretion of hormone by the parathyroid glands. citrate in blood obtained from the spongy bone When the level of serum calcium exceeds of the dog's femur increased strikingly after normal, secretion of parathyroid hormone is injection of parathyroid hormone. They postu- suppressed until the level has returned to normal lated that as a result of accumulation of citrate, (McLean, 1957). These effects have been clearly pH of the fluids surrounding the bone falls, and demonstrated by Copp and Davidson (1961), increased resorption of bone then occurs. The who perfused a dog's parathyroid glands with citrate may also chelate some of the calcium blood of low or high calcium concentration, released by bone resorption, and thus raise the 498 POSTGRADUATE MEDICAL JOURNAL August, 1964Postgrad Med J: first published as 10.1136/pgmj.40.466.497 on 1 August 1964. Downloaded from gradient of ionic calcium between bone and has been shown (Komarkova, Vostal and the surrounding fluid. This theory has led to Pacovsky 1960) that parathyroid hormone a large amount of research into the effect of produces a rise in tissue level of citrate in the parathyroid hormone on the production of kidney. There is some evidence that the level organic acids by Ibone in vitro, and unfortun- of renal citrate controls the tubular reabsorp- ately there has been little agreement between tion of calcium (Karam, Harrison, Hartog and different workers. Massive doses of parathyroid Fraser, 1961), so that an increase in citrate hormone have usually been necessary in order level provides a possible explanation for the to produce an increase in levels of bone citrate, effects of parathyroid hormone on urinary perhaps because of the relatively large amount excretion of calcium. of citrate present in bone in the basal state. Parathyroid hormone probably increases the Moreover, lactate is produced by bone in absorption of calcium from the intestine, but amounts approximately a hundred times less is known about the effect of the hormone greater than those of citrate in response to the on calcium absorption than about that of hormone (Vaes and Nichols, 1961), and it is vitamin D. Rasmussen (1959) showed that therefore possible that lactate is of greater active transport of calcium by segments of rat importance than citrate in producing resorp- duodenum in vitro was increased by parathyroid tion of ,bone. The conflicting results of in vitro hormone. Balance studies in rats (Cramer, studies have been reviewed by Firschein Suiker and Copp, 1961) indicated a marked (1963). Many workers still believe, however, increase in the net absorption of calcium in that parathyroid hormone stimulates the release response to parathyroid hormone, provided of citrate from bone, either by increasing its that intake of calcium was adequate. In Thiry- rate of formation (Ranney, 1960; Lekan, Laskin Vella fistulas in dogs, Cramer (1963) showed and Engel, 1960), or by inhibiting its oxidation that administration of the hormone increasedProtected by copyright. (Neuman and Dowse, 1961; Hekkelman, 1961). absorption of calcium while parathyroidectomy Although the skeleton is probably the most resulted in a decrease. In man, Jaworski, Brown, important site of action for parathyroid hor- Fedoruk and Seitz (1963), using a tracer test mone it is not the only one. There is evidence of calcium absorption with calcium-45, de- that the hormone affects the transport of monstrated increased intestinal absorption of calcium in the kidney, gut and mammary gland. calcium in a patient with hyperparathyroidism. In the kidney, Talbot, Sobel, McArthur and In lactating rats, administration of para- Crawford (1954) first suggested that parathy- thyroid hormone results in a decrease of calcium roid hormone increases the reabsorption of concentration in the milk, while parathyroid- filtered calcium by the renal tubules, so that ectomy leads to increased secretion of calcium, the urinary clearance of calcium is reduced. suggesting that the parathyroid glands inhibit Thus in hypoparathyroidism there may be the secretion of calcium by the mammary gland normal or even high levels of urinary calcium (Toverud, 1963). in spite of hypocalcxmia, while in hyperpara- It can be seen that all the effects of para-http://pmj.bmj.com/ thyroidism, in spite of hypercalcemia, an ab- thyroid hormone described on calcium trans- normally raised urinary excretion of calcium is port lead to an increase in the amount of not always present. Kleeman, Bernstein, Rock- calcium in the blood and body fluids, so that ney, Dowling and Maxwell (1961) showed that through several different mechanisms the para- parathyroid extract produced a significant re- thyroid glands effectively counter falling levels duction in urinary calcium clearance at all levels of serum calcium. From a teleological point of of diffusible calcium, both in the majority of view, it seems most appropriate that calcium, on September 24, 2021 by guest. normal and in hypoparathyroid individuals. made available through resorption of bone, Low clearances of calcium were noted in is not all lost to the body through urinary or patients with primary hyperparathyroidism, and fwecal excretion but is retained in the blood. these rose after removal of the tumour. In The parathyroid has been justly called "glande carefully controlled studies on dogs, in which de protection du capital calcique" (Lichtwitz, filtered loads of other ions were maintained 1961). constant, Widrow and Levinsky (1962) showed Indirect Effects of Parathyroid Hormone on that urinary excretion of calcium fell after Calcium administration of parathyroid extract, although Parathyroid hormone also affects the meta- filtered calcium remained constant or increased. bolism of inorganic phosphorus and probably Similar findings have been reported