Soft-tissue localization of 99mTc-hydroxymethylene diphosphonate due to interaction with calcium

Soft tissue localization of 99mTc-labelled bone imaging agents is often associated with high calcium levels either locally or systemically. This could be due to the formation of a large molecular complex after administration of the radiopharmaceutical. We have investigated the formation of such a complex between 99mTc-hydroxymethylene diphosphonate (HMDP) and calcium by a number of techniques. The results indicate that 99mTc-HMDP is a colloidal preparation which may contain particles up to 280 nm in size, and that the labelled colloid may aggregate in the presence of calcium salts forming particles up to 3 microns. Such particles are too large to permit free diffusion across vascular epithelium but large enough to localize in the liver or lungs. It is suggested that this interaction may be responsible for soft tissue localization of the technetium-labelled bone imaging agents. In vivo the radiolabelled complex in a mixture of 99mTc-HMDP and calcium chloride localizes to a significantly larger extent in liver, spleen and muscle and less in bone compared with 99mTc-HMDP diluted with saline. The increased liver and spleen uptake can be prevented by prior administration of non-radioactive colloid but this does not significantly improve the bone uptake of the 99mTc-HMDP/calcium chloride mixture. The clinical relevance of these findings lies in their possible explanation for soft-tissue uptake and poor bone accumulation of the technetium-labelled diphosphonates in some patients. This may be particularly important in evaluating quantitative bone scans, especially if serial scanning is done to monitor disease progress or therapy since local or systemic calcium levels may change between scans.