Bisphosphonates bind avidly to bone
mineral and are potent inhibitors of osteoclast-mediated bone destruction. They also exhibit antitumor activity in vitro. Here, we used a mouse model of human
breast cancer bone
metastasis to examine the effects of
risedronate and
NE-10790, a phosphonocarboxylate analogue of the
bisphosphonate risedronate, on
osteolysis and
tumor growth.
Osteolysis was measured by radiography and histomorphometry.
Tumor burden was measured by fluorescence imaging and histomorphometry.
NE-10790 had a 70-fold lower bone
mineral affinity compared with
risedronate. It was 7-fold and 8,800-fold less potent than
risedronate at reducing, respectively,
breast cancer cell viability in vitro and bone loss in ovariectomized animals. We next showed that
risedronate given at a low dosage in animals bearing human B02-GFP
breast tumors reduced
osteolysis by inhibiting
bone resorption, whereas
therapy with higher doses also inhibited skeletal
tumor burden. Conversely,
therapy with
NE-10790 substantially reduced skeletal
tumor growth at a dosage that did not inhibit
osteolysis, a higher dosage being able to also reduce bone destruction. The in vivo antitumor activity of
NE-10790 was restricted to bone because it did not inhibit the growth of subcutaneous B02-GFP
tumor xenografts nor the formation of B16-F10
melanoma lung
metastases. Moreover,
NE-10790, in combination with
risedronate, reduced both
osteolysis and skeletal
tumor burden, whereas
NE-10790 or
risedronate alone only decreased either
tumor burden or
osteolysis, respectively. In conclusion, our study shows that decreasing the bone
mineral affinity of
bisphosphonates is an effective therapeutic strategy to inhibit skeletal
tumor growth in vivo.