The development of skeletal metastases.

The search into the way in which skeletal metastases develops has not only shown that there are several mechanisms for the progressive bone destruction and bone formation that occur simultaneously in the majority of skeletal metastases, but also that an understanding of these basic mechanisms has significant therapeutic implications. Our results have shown that there are two main mechanisms for the bone formation: stromal bone formation and reactive bone formation. The former occurs in tumours which tend to be acellular, with a large fibrous stroma, whereas the latter occurs in virtually all metastases. There is no difference in the basic pathological process of sclerotic or lytic metastases, the radiographic appearance purely indicating the net balance between the different types of bone formation and the simultaneous progressive bone destruction. An understanding of the pathophysiological response to skeletal metastases explains why skeletal scintigraphy can be used to diagnose these lesions and the different mechanisms underlying the 'three-phase scintigram'. The first phase indicates the vascularity of the lesion; the second phase or 'blood-pool' image indicates the concentration in the extracellular fluid and the third phase or 'skeletal or delayed image' indicates the uptake in the reactive new bone. The secretion of an osteoblast inhibiting factor by myeloma indicates why there is no reactive bone produced by the majority of lesions in the absence of a fracture, and why scintigraphy is less reliable than plain radiographs for the detection of the lesions. There are two main mechanisms for the bone destruction, the most important being mediated via osteoclasts. An understanding of the humoral mechanisms stimulating the osteoclast proliferation may lead to more effective treatment of malignant hypercalcaemia and lytic metastases. Early results of use of APD are encouraging, and our results also suggest that clinical trials should be established to evaluate the effect of combination therapy with APD or prostaglandin inhibitor combined with the agents normally used in the management of patients with disseminated mammary carcinoma. The development of treatments to inhibit tumour-induced osteolysis will minimise the complications of pathological fracture, spinal instability, etc., and even if these treatments do not affect the primary tumour, its ability to metastasize, or the patient's survival, such treatment will be a major advance in the management of patients with carcinoma, because of the significant morbidity currently associated with the development of skeletal metastases and their complications.(ABSTRACT TRUNCATED AT 400 WORDS)