Pro‐osteolytic effects of chronic morphine administration in a model of breast cancer‐induced bone pain.

Abstract

Many common cancers have a high propensity for bone metastasis; for breast cancer, bone metastasis affects 70% of advanced patients and is the most common site for secondary tumor relapse. Tumor manifestation disrupts bone homeostasis and results in debilitating chronic skeletal pain that decreases patient functional status, quality of life and survival. Morphine remains the golden standard for managing cancer‐induced bone pain; however, opioids including morphine are associated with a host of side effects that complicate chronic dosing schedules. Furthermore, it has been posited that morphine may accelerate bone wasting in patients; in models of secondary bone metastasis, morphine exacerbates fracture rate, markers of osteolysis, and pain behaviors.We sought to determine whether morphine exacerbates bone loss in the 66.1‐Balb/C model of breast cancer‐induced bone metastasis (BCBM). Sham and tumor‐inoculated animals received a constant morphine infusion for 7 days (20 mg/kg/day). Morphine produced initial analgesia but failed to manage behaviors indicative of cancer‐induced bone pain over time; additionally, morphine treatment increased TRACP 5b in sera and RANKL in femur extrudate, suggesting that morphine enhances osteolysis in BCBM. In vitro studies evaluated the ability of morphine to induce osteoclastogenesis in the presence of permissive levels of RANKL. Morphine did not appear to affect tumor burden in vivo or in vitro viability of tumor cells. These data suggest that morphine worsens bone loss in the 66.1‐Balb/C model and may act directly on osteoclast cells; however, the exact mechanism of morphine‐induced bone loss is unknown and remains a barrier to improving pain relief in suffering BCBM patients.