MECHANISMS OF CALCIUM DEFICIENCY DISEASE
In regulating ECF [Ca2+J, and specifically in adapting to iow calcium intake, effects occur just for bone health but for nonskeletal systems such as blood pressure and body fat regulation. Adaptation, although obviously a necessary capacity, may neverth~less exert desirable effects when constantly invoked. In addition to sustaining ECF [Ca2+] by thdrawing calcium from the reserve, PTH elicits responses in extra skeletal tissues that .y be inappropriate. Medical science is familiar with this phenomenon in the case of stress-with its high adrenergic hormone levels and high secretion of adrenal glucocorticoids.
Less well understood, but gradually becoming clearer, are the counterpart effects following from constant high secretion of PTH with its cascade of mechanisms. First is an increase in -'\..e parathyroid cell mass itself. Associated with this phenomenon is an age-specific increase incidence of hyperparathyroidism among postmenopausal women. Whether the two phenomena are causally related is not settled, but it is true for other organ systems that nstant stimulation promotes neoplasia, and it would be surprising if this relationship were ot true for the parathyroid glands as well. All of the disorders currently linked to calcium relate either to decrease in the size of the calcium reserve, to decrease in residual calcium in ·\..e intestinal contents as they reach the lower bowel, or to nonskeletal responses to the rmones mediating adaptation to low calcium intake.
Osteoporosis is the disorder that results when the size of the calcium reserve the skeleton) is depleted for nutritional reasons. (As described briefly below, osteoporosis has
;her causes as well.) The hormonal responses regulating ECF [Ca2+] succeed in maintaining :hat critical value, but they do so by depleting the nutrient reserve (bone mass). The risk of both colon cancer and kidney stones rises as the calcium content of the diet residue falls, both for the same basic reason: failure to complex potentially harmful chemicals in the food residue.
The best available explanation for the remaining disorders lies in the fact that, in addition to its classical effects regulating ECF [Ca2+], PTH and/or 1, 25(OH)2D elevate cytosolic calcium ion concentrations in many tissues, thereby altering their basal level of functional activity. Hyperparathyroidism, listed as a consequence of the adaptive mechanism, is placed in parentheses because the evidence linking this disorder to low calcium intake is less clear than for the other disorders.
The first two mechanisms are straightforward, related directly to reduction in calcium mass-either the total body mass difference between calcium absorption and calcium excretion or to the mass of calcium in the intestine left over from the diet. Both are inescapable aspects of low intake. The mechanisms for the other disorders are more subtle and are set forth schematically. In addition to the effect of PTH on cytosolic calcium concentration, expression of these disorders almost certainly requires other defects. The constant high blood PTH level and the consequent high blood 1, 25(OH)zD level stress the system beyond the reserve capacity of sensitive individuals. In this sense, such response to chronically high PTH levels is analogous to the hemolytic anemia that develops, for example, on exposure to certain drugs or to fava beans in individuals with glucose-6-phosphate dehydrogenase deficiency.
In the absence of a stressor agent, little or no clinical evidence of anemia is present.
Presumably, the disorders that follow on a hypersensitivity to PTH and/or 1, 25(OH)2D manifest themselves in individuals who lack sufficient redundancy in the cell control mechanisms to compensate for the unsignalled elevation in cytosolic calcium ion concentration.
At the same time, it must also be emphasized that all of the disorders in all three categories are, in their own right, multifactorial. For example, there are many ways to have a reduced skeletal mass in addition to inadequate nutrient intake, and there are many ways to have
elevated blood pressure in addition to high endogenous PTH levels. Thus, low calcium intake is only one factor in the genesis of these disorders, and if one could optimize calcium intake in the entire population, it is certain that none of the diseases concerned would be totally dicated. Nevertheless, altering calcium intake will reduce the total disease burden for all these disorders. Furthermore, doing so is a cost-effective intervention within society's grasp, md one that therefore demands attention.
