Abstract
BackgroundThe bisphosphonate, zoledronic acid (ZOL), can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice.MethodsThe model involves intracardiac injection for arterial dissemination of the RM1(BM) cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 µg/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate-resistant acid phosphatase 5b (TRAP 5b) and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots.FindingsMicro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM) cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice.ConclusionsZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a requirement for establishment of these bone tumours.
Highlights
Some primary cancers have a high propensity to metastasise to bone but the reasons for this remain unclear, it is generally accepted that growth of most cancers in bone is dependent on factors present in the bone micro-environment
Bone involvement is common in prostate and breast cancers and myeloma, and while breast cancer and myeloma bone-metastases are predominantly osteolytic, involving increased osteoclast activity leading to bone erosion, prostate cancer bone metastasis cases are heterogeneous, involving both bone lytic and sclerotic effects [2]
We demonstrate that inhibition of osteolysis with zoledronic acid (ZOL) treatment does not influence incidence of bony tumours
Summary
Some primary cancers have a high propensity to metastasise to bone but the reasons for this remain unclear, it is generally accepted that growth of most cancers in bone is dependent on factors present in the bone micro-environment. Cancer cells can produce cytokines that promote osteoclast differentiation directly [3,4] and indirectly through stimulation of bone marrow stromal cells to promote osteoclastogenesis [5]. Tumour cells can produce cytokines that promote osteoblast activity and induce bone growth [6] and osteoblasts can induce cancer development and progression [7,8,9]. We used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice
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