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Measuring what isn't there.

In the rush to develop “peaceful uses of the atom” in the years following testing of the H-bomb, much interesting work was done with radioactive calcium isotopes (45Ca and 47Ca). Perhaps most important was the finding that the relatively huge quantities of calcium contained in mature bone exchanged only negligibly with calcium either in extracellular fluid (ECF) or in immediately adjacent bone (1). This meant that tracer uptake by bone could be used as a direct measure of new bone mineralization. Although various complicated kinetic models were developed(2)(3), the mathematics were actually quite straightforward. The tracer content of a sample of bone calcium obtained days or weeks after an injection of a calcium isotope into an animal, divided by the average tracer concentration in ECF calcium, directly yields the mass of calcium deposited by bone formation during the interval between tracer injection and the time of the bone sampling.

What was missing from the picture was the ability to measure the other half of the bone remodeling/modeling process, i.e., bone resorption. How could one measure in a bone what was no longer there? Measuring the decrease in bone tracer content was not a feasible approach because the resorptive process removes mainly older bone, which contains little or no tracer. Despite this barrier and because so much of the interest in clinical bone biology was focused on bone resorption, there has for years been a search for a more “direct” quantification of the process. This quest was reinforced by the development of antiresorptive pharmacologic agents for the treatment of osteoporosis, as well as by the demonstration that resorption responds sensitively to environmental or physiologic signals, whereas bone formation tends to be relatively invariant over the short term (4).

Moreover, the investigational focus shifted from in …