Effect of the bisphosphonate risedronate on bone metastases in a rat mammary adenocarcinoma model system

Abstract

Risedronate (NE-58095) is a third-generation bisphosphonate with very potent antiresorptive activity but few toxic effects. The purpose of this work was to evaluate the effect of risedronate treatment on bone metastases produced in a rat breast cancer model. Berlin Druckrey IV rats inoculated with ENU1564 mammary adenocarcinoma cells were treated daily with risedronate or a saline placebo. Survival times, dictated by extraskeletal metastases (lung, heart, and brain), were not affected by risedronate treatment. Risedronate-treated animals had skeletal changes associated with decreased remodeling of bones undergoing endochondral ossification, most prominently affecting the appendicular skeleton. Despite the skeletal alterations induced by the treatment, the distribution of bone metastases throughout the surveyed skeletal sites was similar for treated and untreated animals. Bone metastases were enumerated in histologic sections of distal femur, spine, and skull. Tumor size was estimated from area measurements obtained from histologic lesions in distal femoral metaphyses and vertebral bodies. A greater number of treated rats had no bone metastases in any of the examined sections (30 versus 16.1% of untreated rats). Multiple bone metastases were observed less frequently in treated rats (33.3 versus 71% of untreated rats). Treated rats had fewer observed bone metastases in each examined site than untreated rats (p < or = 0.025). Mean tumor areas in femora and vertebrae were smaller in treated rats (p < or = 0.05), due to the less frequent presence of very large lesions. In untreated animals, osteoclasts appeared to be active at the tumor/bone interface and osseous structures were often completely replaced by expanding tumors. In contrast, metastases in treated animals caused less disruption of skeletal histoarchitecture. The apparent lack of osteoclastic activity and retention of bone within lesions suggested a decreased contribution of osteoclasts to the bone resorptive process. An in vivo immunohistochemical cell proliferation assay failed to reveal differences in the percentage of dividing tumor cells in bone metastatic sites in treated versus untreated animals. The results demonstrate significant effects of risedronate treatment on the incidence and size of observed skeletal metastases in this model.

Animal Models of Bone Metastasis

“…When injected into the left ventricle of the heart of Berlin-Druckrey IV rats, osteolytic metastases developed in the femur, spine, and skull. 39 …”

Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments

“…The anti-proliferative, anti-angiogenic and apoptotic properties (see Clezardin 2011 for review) of BPs is supported by efficacy data from rodent models (Hall and Stoica 1994; Yoneda et al 1997; Clohisy et al 2001). …”

Sequential design for nonparametric inference

“…Several studies during the past two decades have clearly demonstrated that a variety of bisphosphonates can reduce tumor‐induced osteolysis in animal models of breast,43–52 prostate,33, 53–60 and bladder cancer,61–64 as well as multiple myeloma 42, 65–69. By inhibiting osteoclast‐mediated bone resorption, bisphosphonates decrease the release of tumor‐promoting growth factors from bone and delay the further progression of bone metastases.…”