Strontium as a tracer for calcium in biological and clinical research.

The calcium ion is required for the operation of a number of physiological processes, such as bone and tooth formation, blood coagulation, nerve impulse transmission, and muscle contraction. At the cellular-biochemical level, the calcium ion participates in signal transduction and is a significant factor in cell replication and cell division. The ultimate source of this important element is the diet, and the proper absorption of calcium is required to meet body needs. Abnormal or inadequate calcium absorption is a contributing factor in certain disease states, including osteoporosis, vitamin D-deficiency rickets, vitamin Ddependent rickets types I and II, and chronic renal failure, to name a few. The continued study of calcium absorption and calcium metabolism in animals and humans is essential for further elucidation of basic mechanisms, for understanding of disease processes, and for assessment of the efficacy of therapeutic strategies. Importantly, the use of tracer methodologies in studies of calcium metabolism has provided valuable information not otherwise attainable. The radionuclides of calcium that have been widely used with considerable advantage as tracers in the study of calcium and bone metabolism are the beta-emitting Ca and the gamma-emitting Ca. However, the use of radioactive substances in basic and clinical research is dwindling because of the costs of radionuclides, the costs of disposal of radioactive wastes, and the justifiable reticence of giving potentially hazardous radionuclides to human subjects, particularly to the young and the pregnant. Stable isotopes of calcium are available that have been beneficially used in human and animal studies but here the disadvantages are the cost of the stable isotopes of calcium (Ca, Ca) and the more specialized equipment required for their analysis. For these and other reasons, researchers have turned to the use of strontium as a surrogate for calcium. The strontium and the calcium ions, members of the alkaline earth series (Group IIB of the Periodic Table), have many properties in common, both having a valency of 21, similar ionic radii, and the ability to form complexes and chelates of various solubilities and various binding strengths. The relative binding affinity of Ca and Sr differs among anionic compounds, some preferring Ca and others Sr. The binding of Sr to alginates exceeds that of Ca by factors of 1.5 to 4.3, whereas calcium is preferred in other interactions, e.g., binding to G-actin, blocking negative charges on membranes, and binding to collagen [1]. In most biological systems, preference in general is given to Ca over Sr, although a marine organism, an Acantharia, constructs its internal skeleton of strontium sulfate [2]. In higher vertebrates, the bony skeleton is mostly composed of the highly insoluble calcium phosphate complex, hydroxyapatite. Strontium present in bone is usually considered a contaminant, with no physiological function at the trace values present therein. However, the usefulness of strontium as a potential therapeutic agent for osteoporosis has experimental support. For example, in recent studies, low doses of strontium are reported to have beneficial effect on bone formation in osteoporotic patients and, in some studies, strontium has been given as a salt, designated S 12911 [3, 4]. The upswing in interest in strontium as a useful analog of calcium in clinical research was preceded by the development of a large body of information prompted by the formation of radionuclides of strontium as byproducts of nuclear fission and atomic bomb detonation. Sr and Sr are the prominent radionuclides of strontium that are formed, with Sr being one of the most hazardous because of its deposition in the skeleton, its long biological half-life (;10 years), and a decay half-life of ;30 years. A major purpose of the earlier investigations was to find procedures for decreasing the body burden of radiostrontium in the event of contamination of the environment and food supply [5]. Although the preferential movement of calcium over strontium between compartments in biological systems has long been known, a primary objective of many studies in the 1950s and 1960s was to quantify the relative movement and the retention of these alkaline earth cations, and to devise procedures to minimize the body burden of radiostrontium. Concepts were developed to formalize the relationships between Ca and Sr in their progress along the food chain to humans. The degree of discrimination was defined by the ratio of Sr/Ca in one compartment with respect to a precursor compartment. For example, experimental studies showed that the Sr/Ca ratio in milk was 0.1 with respect to the ultimate precursor, the diet, for which the Sr/Ca ratio was assigned the value of 1.0 [6]. This means that calcium is enriched 10-fold over strontium in the transfer from diet to milk—because of the preferential translocation of Ca over Sr in the processes of intestinal absorption, renal tubular reabsorption, and milk secretion. Calcium also moves more rapidly than Sr across the placenta from dam to fetus [7]. Little discrimination occurs in the transfer of Ca and Sr from blood to bone [6]. Quantitatively, the discrimination of calcium over strontium during the course of absorption varies among vertebrate species and ranges roughly from 2.4 to 5.0 [8]. Lengemann [8], in his review, noted that increases in dietary calcium decreased the fractional absorption of both elements proportionately, that the relative absorption of Ca and Sr tracers was not appreciably different in different segments of the small intestine (duodenum, jejunum, ileum) despite differences in the degree of fractional absorption, and that vitamin D similarly increased the absorption of Ca and Sr (i.e., there is no apparent vitamin D-dependent change in the preferential absorption of Ca over Sr). Because of the high degree of absorption of calcium in infants, particularly from milk Editorial