Regulation of Extracellular Fluid Calcium Concentration
A central feature of the calcium economy of all mammals is the tight control of calcium in extracellular fluid (ECF). This comes about by adjusting both the renal calcium threshold and the flows of calcium into and out of the ECF. These processes, in turn, are regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D [1, 25(OH)2D], and calcitonin. PTH acts to correct a fall in calcium concentration by a complex set of interacting effects. These actions include, in the probable order of the appearance of their effects, decreased renal tubular reabsorption of blood inorganic phosphate, increased resorptive effi-ciency of osteoclasts already working on bone surfaces, increased renal1-a-hydroxylation of circulating 25(OH)vitamin D to produce the chemically most active form of vitamin D, increased renal tubular reabsorption of calcium, and activation of new bone remodeling loci. These effects interact and reinforce one another in important ways.
For example, the reduced ECF phosphate caused by the immediate fall in tubular reabsorption of phosphate is itself a potent stimulus to the synthesis of 1,25(OH)2D, and it also increases the resorptive efficiency of osteoclasts already in place and working in bone, and thereby augments their release of calcium from the bony reserves. The 1, 25(OH)2D directly increases intestinal absorption of both calcium ingested in food or supplement form and the endogenous calcium contained in the digestive secretions; it also is necessary for the full expression of PTH effects in bone, particularly the maturation of cells in the myelomonocytic line that produce new osteoclasts. Although a great deal more complicated in detail, these actions amount to three effects: reduced losses through the kidneys, improved utilization of dietary calcium, and withdrawal of calcium from the bony reserves.
The aggregate effect of all three is to prevent or reverse a fall in ECF [Ca2+] and, at a whole body level, to conserve calcium in the face of an environmental shortage. However, the first of these takes priority, i.e., the maintenance of ECF [Ca2+] occurs at the expense of the skeletal reserve. A key feature of the triple end organ response to the calcium-conserving action ofPTH is the balance between the three responses, and particularly the relative sensitivity, of the internal (bone) and the external (gut, kidney) effector organs. In blacks, for example, th~ bony effects are relatively resistant to PTH (1 - 3).
In order to maintain ECF [Ca2+], Blacks must secrete more PTH and 1, 25(OH)2D, which produce a correspondingly greater absorptive response at the gut and a greater calciumconserving response at the kidney. This explains why, despite lower mean calcium intakes, blacks nevertheless develop and maintain skeletons approx 10% more dense than Caucasians or Asians. A similar, although smaller, difference exists between pre- and postmenopausal women. In the presence of estrogen, bone is slightly more resistant to PTH, which explains why the calcium requirement for skeletal maintenance rises after menopause.
