Extending preclinical models of skeletal manifestations of malignancy to the clinical setting

There is a spectrum of presentations of skeletal manifestations of malignancy that includes generalized osteopenia and hypercalcemia, focal osteolysis, focal osteogenesis, and osteomalacia and hypophosphatemia. In various preclinical animal models, parathyroid hormone-related protein (PTHrP) was seen to be produced by tumor cells, causing osteolytic lesions, either with or without hypercalcemia. EB1089, an analog of 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3], when used as a potential therapeutic agent, decreased both the number and size of metastatic bone lesions, the incidence of hind limb paralysis, and the volume of tumor burden within the bone, and also prolonged survival time. These findings were attributed to the interruption of pathways leading to PTHrP production. From studying osteoblastic metastases of prostate cancer in preclinical animal models, urokinase expression by the tumor was proposed as a growth factor and as an activator of other bone growth factors; however, the mechanism of action of osteoblastic metastases requires further research. The design of suitable preclinical animal models to study the pathophysiology of oncogenic osteomalacia also needs further investigation, though a genetic model of hypophosphatemic osteomalacia exists. The animal models and study designs used all establish methodologies that can be adapted for use in future clinical trials.